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Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR–Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE.

COVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications1,2. Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs 3–5). Although rapid induction of type I IFNs limits virus propagation, a sustained increase in the levels of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome5–17. Here we show that the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, which controls immunity to cytosolic DNA, is a critical driver of aberrant type I IFN responses in COVID-19 (ref. 18). Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature that is primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS–STING activity was detected in lung samples from patients with COVID-19 with prominent tissue destruction, and was associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, infection with SARS-CoV-2 activates cGAS–STING signalling in endothelial cells through mitochondrial DNA release, which leads to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a principle for the development of host-directed therapeutics.

Autoinflammation is a sterile inflammatory process resulting from increased neutrophil infiltration and overexpression of IL-1 cytokines. The factors that trigger these events are, however, poorly understood. By investigating pustular forms of psoriasis, we show that human neutrophils constitutively express IL-26 and abundantly release it from granular stores upon activation. In pustular psoriasis, neutrophil-derived IL-26 drives the pathogenic autoinflammation process by inducing the expression of IL-1 cytokines and chemokines that further recruit neutrophils. This occurs via activation of IL-26R in keratinocytes and via the formation of complexes between IL-26 and microbiota DNA, which trigger TLR9 activation of neutrophils. Thus our findings identify neutrophils as an important source of IL-26 and point to IL-26 as the key link between neutrophils and a self-sustaining autoinflammation loop in pustular psoriasis.

This study investigates the recent extreme temperature trends across 19 stations in the Klang Valley, Malaysia, over the period 2006–16. Fourteen extreme index trends were analyzed using the Mann-Kendall non-parametric test, with Sen’s slope as a magnitude estimator. Generally, the annual daily mean temperature, daily mean maximum temperature, and daily mean minimum temperature in the Klang Valley increased significantly, by 0.07°C yr−1, 0.07°C yr−1and 0.08°C yr−1, respectively. For the warm temperature indices, the results indicated a significant upward trend for the annual maximum of maximum temperature, by 0.09°C yr−1, and the annual maximum of minimum temperature, by 0.11°C yr−1. The results for the total number of warm days and warm nights showed significant increasing trends of 5.02 d yr−1and 6.92 d yr−1, respectively. For the cold temperature indices, there were upward trends for the annual minimum of maximum temperature, by 0.09°C yr−1, and the annual minimum of minimum temperature, by 0.03°C yr−1, concurrent with the decreases in the total number cold days (TX10P), with −3.80 d yr−1, and cold nights (TN10P), with −4.33 d yr−1. The 34°C and 37°C summer days results showed significant upward trends of 4.10 d yr−1and 0.25 d yr−1, respectively. Overall, these findings showed upward warming trends in the Klang Valley, with the minimum temperature rate increasing more than that of the maximum temperature, especially in urban areas.

Detection of myocardial perfusion abnormalities using Tc-99m tetrofosmin was evaluated for sensitivity and specificity compared to coronary angiography. Between January 1996 and January 1998, exercise stress tests and myocardial scintigraphy were performed in 58 patients, followed by coronary angiography within 2 months. There were 48 males and 10 females, aged 33 to 72 years (mean, 57 years). The sensitivity and specificity of exercise stress tests were 64% and 68%, respectively, while the sensitivity and specificity of Tc-99m tetrofosmin scans were 88% and 75%, respectively, compared to angiography. For Tc-99m tetrofosmin scans, the sensitivity was 78% for the left anterior descending artery, 66% for the left circumflex artery, and 76% for the right coronary artery; specificity was 74% for the left anterior descending artery, 90% for the left circumflex artery, and 75% for the right coronary artery. It was concluded that Tc-99m tetrofosmin allowed high-quality myocardial perfusion imaging with results comparable to those obtained using thallium-201 chloride.